MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes
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Background: Chronic skin inflammation in atopic dermatitis (AD) is associated with elevated expression of proinflammatory genes and activation of innate immune responses in keratinocytes. microRNAs (miRNAs) are short, single-stranded RNA molecules that silence genes via the degradation of target mRNAs or inhibition of translation. Objective: The aim of this study was to investigate the role of miR-146a in skin inflammation in AD.
Results: We show that miR-146a expression is increased in keratinocytes and chronic lesional skin of patients with AD. miR-146a inhibited the expression of numerous proinflammatory factors, including IFN-γinducible and ADassociated genes CCL5, CCL8, and ubiquitin D (UBD) in human primary keratinocytes stimulated with IFN-γ, TNF-α, or IL-1β. In a mouse model of AD, miR-146adeficient mice developed stronger inflammation characterized by increased accumulation of infiltrating cells in the dermis, elevated expression of IFN-γ CCL5, CCL8, and UBD in the skin, and IFN-γ IL-1β, and UBD in draining lymph nodes. Both tissue culture and in vivo experiments in mice demonstrated that miR-146amediated suppression in allergic skin inflammation partially occurs through direct targeting of upstream nuclear factor kappa B signal transducers caspase recruitment domain- ontaining protein 10 and IL-1 receptorassociated kinase 1. In addition, human CCL5 was determined as a novel, direct target of miR-146a.
Conclusion: Our data demonstrate that miR-146a controls nuclear factor kappa Bdependent inflammatory responses in keratinocytes and chronic skin inflammation in AD.
| Original language | English |
|---|---|
| Journal | Journal of Allergy and Clinical Immunology |
| Volume | 134 |
| Issue number | 4 |
| Pages (from-to) | 836-847.e11 |
| ISSN | 0091-6749 |
| DOIs | |
| Publication status | Published - 1 Oct 2014 |
Bibliographical note
Funding Information:
This work was supported by the Swiss National Science Foundation (grant no. 32-132899 and grant no. 32-112306 ), the Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland (CK-CARE), Swiss-Polish contribution , the Estonian Science Foundation (grant no. ESF8350 and grant no. ESF7437 ), European Regional Fund with Archimedes Foundation , European Union structural assistance grant (grant no. SARMP12219T ), institutional research grant (grant no. IUT2-2 ), and personal research grants (grant no. PUT214 and grant no. PUT177 ) from the Estonian Research Council . A. Rebane was supported by fellowships from the SCIEX Program NMS-CH and ESTBIOREG .
Funding Information:
Disclosure of potential conflict of interest: M. Zimmermann has received research support from SNF . M. P. Boldin is employed by City of Hope, has received research support from the Tim Nesvig Lymphoma Foundation , and has stock/stock options in Regulus Therapeutics. C. A. Akdis has received research support from Novartis , PREDICTA , the Swiss National Science Foundation , Mechanisms of the Development of ALLergy , the Christine Kühne Center for Allergy Research and Education (CK-CARE), and Swiss-Polish Research Cooperation ; has received consultancy fees from Actelion , Aventis , Stallergenes , Allergopharma , Circasia , and Anergis ; and is employed by the Swiss Institute of Allergy and Asthma Research. The rest of the authors declare that they have no relevant conflicts of interest.
Publisher Copyright:
© 2014 American Academy of Allergy, Asthma and Immunology. Methods: RNA and protein expression was analyzed using miRNA and mRNA arrays, RT-quantitative PCR, Western blotting, and immunonohistochemistry. Transfection of miR- 146a precursors and inhibitors into human primary keratinocytes, luciferase assays, and MC903-dependent mouse model of AD were used to study miR-146a function.
- Allergy, atopic eczema, gene therapy, noncoding RNA
Research areas
ID: 315464394